NR AXVE
AU Rincon-Limas,D.; Casas-Tinto,S.; Nino-Rosales,M.L.; Gomez-Velazquez,M.; Castilla,J.; Soto,C.; Fernandez-Funez,P.
TI Hsp70 Prevents PrP Misfolding and Protects Drosophila Neurons against PrP Neurotoxicity
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Oral Abstracts FC4.7
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Vortrag
AB Prion diseases are a group of lethal neurodegenerative disorders affecting humans and animals and are associated to PrPsc deposition in the brain. It is clear that misfolding and conversion of the normal prion protein (PrPc) into the pathogenic PrPsc is a key event leading to rapid spongiform neurodegeneration and death. Unfortunately, a major gap exists in our understanding of how the conformational conversion of PrP occurs and how it ultimately kills neurons. Recent in vitro studies suggest that molecular chaperones may be key factors mediating PrP misfolding. However, the functional relevance of this finding is unknown since chaperone activity has not been manipulated in animal models of prion diseases. To gain insight into the in vivo role of Hsp70 in PrP misfolding, we created a Drosophila model of sporadic prion conversion. In transgenic flies, wild type PrP from hamster accumulates in membranous structures associated to the Golgi and the secretory machinery, as well as in the cellular membrane. PrP-expressing flies display axonal degeneration and neuronal cell loss associated to progressive PrP insolubility and fibrillar deposition of PrP. Fly-produced PrP exhibits conformational features consistent with PrPsc from infected hamsters, as evidenced by guanidine denaturation and immunoreactivity to PrPsc conformational antibodies. When human Hsp70 was expressed in our PrP flies, we found that Hsp70 colocalizes with PrP aggregates and prevents misfolding. Strikingly, overexpression of human Hsp70 also protects against PrP-dependent neurodegeneration in the fly brain. Thus, we propose that Hsp70 and other molecular chaperones can potentially alleviate PrP neurotoxicity in prion diseases. Finally, our data indicate that Drosophila is an ideal system to genetically dissect fundamental, unknown aspects of PrP-associated pathology.
AD D. Rincon-Limas, S. Casas-Tinto, M.L. Nino-Rosales, M. Gomez-Velazquez, C. Soto, P. Fernandez-Funez, University of Texas Medical Branch, Neurology, USA; J. Castilla, Scripps Research Institute, USA
SP englisch
PO Schottland